It is generally accepted that the abilities to learn and remember arise through activity-dependent modifications in the properties of the neural circuits underlying behavior. The outputs of neural circuits depend on an interplay between synaptic connections and the intrinsic firing properties of individual neurons, but despite the importance of these intrinsic neuronal properties for circuit function, studies on the mechanisms of learning have stressed almost exclusively the role of synaptic modifications. We have shown that isolated lobster stomatogastric ganglion neurons in culture undergo activity-dependent transitions between tonic firing and burst firing states in a calcium-dependent manner. These transitions are produced by regulation of the expression of ionic conductances. These studies indicate that the intrinsic firing properties of neurons, like synaptic strengths, can be continuously modified by ongoing activity, and that the firing properties of a neuron are in part a function of its recent history of activation. This proposal will follow up on these findings by using electrophysiological and calcium imaging techniques to address the mechanisms by which activity modifies intrinsic neuronal firing properties. The role of intracellular calcium, protein synthesis, and protein kinases in this process will be addressed. We will determine whether local activation of individual neurites can locally modify the magnitude or distribution of conductances, and whether this modification acts to oppose or to potentiate synaptic inputs. The long-term goal of this proposal is to understand how intrinsic neuronal properties and synaptic strengths are conjointly regulated to encode experience. In order to study the interactions between intrinsic and synaptic plasticity, we have begun to develop a cortical culture system in which the firing properties and synaptic properties of specific populations of neurons can be studied, and where spontaneous synaptic activity is high. The additional time for research afforded me by the award of a K02 grant will allow me concentrate my personal effort on developing this new culture system. I believe this system will provide essential information about the building blocks of learning and memory, and the role of experience in determining and modifying nervous system structure and function.